NORD gratefully acknowledges Frederick S. Kaplan, MD, Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine; Chief, Division of Orthopaedic Molecular Medicine and Director, Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania and Eileen M. Shore, PhD, Cali/Weldon Professor of FOP Research, Departments of Orthopaedic Surgery and Genetics, and Co-Director, Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, for assistance in the preparation of this report.
Progressive osseous heteroplasia (POH) is an extremely rare disorder characterized by abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification). The disorder first appears as areas of patchy bone formation (ossification) in the skin during infancy; heterotopic ossification progresses to involve superficial and deep connective tissues, including areas of fat beneath the skin (subcutaneous fat), muscles, tendons, ligaments, and the sheets of fibrous tissue that envelop muscle (fascia). This abnormal formation of bone may restrict the movement of affected joints and/or hinder the growth of affected limbs. The course of the disease is unpredictable; some areas of the body may become severely affected while others may remain unaffected. A diagnosis of POH is made only if the bone formation progresses to the deeper connective tissues. Otherwise, the bone formation is classified as osteoma cutis.
The symptoms of POH are usually present at birth (congenital) or within the first few weeks of life, and they tend to progress slowly and asymmetrically as an affected individual grows older. Infants with POH typically have a maculopapular rash (with patchy areas of bone within the dermis). Initially, affected skin may feel abnormally rough.
The major finding in infants with POH is the development of extra-skeletal bone (heterotopic ossification). Initially, bone growth may develop within the skin (osseous nodules or plaques called osteoma cutis). These areas may become progressively widespread and may grow together (coalesce) to form even larger areas of hardened and thickened skin (dermal ossification). As the disease progresses, these bony growths may extend into the deeper layers of the skin (subcutaneous layers). Eventually, abnormal bony growths occur in various connective tissues of the body such as fascia and skeletal muscle.
Children with osteoma cutis or POH may also have sharp, needle-like projections of bone (spicules) that break through the surface of the skin, causing irritation or superficial infection.
As the abnormal development of bone progresses, it may restrict movement of joints and eventually lock the joints (ankylosis). POH may also restrict movement in any area of the body. Affected arms and legs may become malformed and not grow to full length. This can occur on one side of the body and lead to unequal growth; one leg or one arm may become shorter than the other, for example. Some areas of the body may be severely affected, while other areas may remain unaffected. In some patients, lesion formation occurs predominantly or exclusively on one side (either left or right) of the body (hemimelic progressive osseous heteroplasia).
In addition, when bone growth occurs around the spine, some affected individuals may develop an abnormal sideways curvature of the spine (scoliosis).
The progression of POH is highly variable even among members of the same family. In some individuals, it may progress extremely slowly; in others it may progress more rapidly. Most individuals experience a gradual progression of the condition.
Heterotopic bone formation in POH may be more intramembranous than endochondral in nature, and no inflammatory component has been identified. Histologically, bone can be seen to arise directly within adipose stromal tissue although the exact cell(s) of origin remain unknown.
In addition to induction of extra-skeletal bone formation, inactivating mutations in the GNAS gene have been associated with altered skeletal bone quality in mouse models. Detailed studies of skeletal bone quality in POH remain to be thoroughly investigated.
Some cases of POH may be caused by disruption or changes (mutations) of the GNAS gene. About three-fourths of examined POH patients have inactivating GNAS gene mutations.
The GNAS (guanine nucleotide-binding protein, alpha-stimulating polypeptide) gene contains instructions for producing (encoding) a protein that researchers believe may be involved in regulating the activity of proteins (produced by other genes) that promote bone growth and direct cell fate decisions. In POH, mutation of the GNAS gene results in deficiency or dysfunction of the Gsα protein. The exact manner in which mutations of the GNAS gene bring about the symptoms of POH is not yet known, however evidence implicates activation of the “hedgehog” signaling pathway in this process.
Most cases of POH occur randomly as the result of a spontaneous (sporadic) genetic change (new mutation) of the GNAS gene. However, this mutation can also be inherited from a parent and follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease.
A specific gene regulation process associated with POH is known as genetic imprinting. Everyone has two copies of every gene (except for genes on X and Y chromosomes) – one received from the father and one received from the mother. In most cases, both gene copies can be “turned on” and are active. However, some genes are maintained as preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical regulation through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several human diseases including POH. In individuals with POH, the defective copy of the GNAS gene is inherited from the father. If a defective GNAS gene is inherited from the mother, individuals typically develop related, yet clinically distinct, disorders known as Albright hereditary osteodystrophy (AHO) and/or pseudohypoparathyrodism type 1a (PHP1a).
More than 50 affected individuals with POH have been identified around the world. Although the majority of the cases initially reported occurred in females, the disorder appears to affect males and females in similar numbers. Because POH often goes unrecognized or misdiagnosed, determining the true frequency of the disorder in the general population is difficult. In the most severe cases, symptoms are usually apparent at birth or within the first few weeks of life. Symptoms usually progress as affected individual’s age.
POH was first described in 1994.
The diagnosis of POH may be confirmed by a thorough clinical evaluation, characteristic physical findings, and tests that demonstrate the presence of heterotopic ossification (e.g., x-ray or roentgenograms and CT scans) with characteristic appearance for POH in the deep connective of the fascia, muscles, tendons, muscles and/or ligaments.
Special shoes, braces, and other devices to assist in walking and weight-bearing have been used to help people with POH involving the lower limbs. Occupational therapy evaluations and appropriate assistive devices for activities of daily living may be helpful for those in whom POH involves the upper limbs. Immunizations should be given on areas of the skin that are unaffected by the bony growths that are prevalent with this disorder. Other treatment is symptomatic and supportive. A team approach for infants with this disorder will be of benefit and may include special social, educational, and medical services.
Genetic counseling is recommended for affected individuals and their families.
Surgery, radiation therapy, and several different types of drugs have been used to treat disorders involving the abnormal development of bone (heterotopic ossification) but are ineffective in POH. Surgery to remove heterotopic bone characteristically exacerbates POH. Surgical removal of ectopic bone has provided only temporary relief in some cases; in other cases, the improper bone growth has recurred massively after the surgery. Extreme caution should be used in considering surgery for individuals affected by POH. It is rarely indicated. More research must be conducted to determine the effectiveness of radiation and various drug therapies when used to treat POH.
Contacts for additional information about progressive osseous heteroplasia:
For basic research questions:
Eileen M. Shore, PhD
Professor, Departments of Orthopaedic Surgery and Genetics
Perelman School of Medicine
University of Pennsylvania
309A Stemmler Hall
3450 Hamilton Walk
Philadelphia, PA 19104-6081
email: [email protected]
For clinical questions:
Frederick S. Kaplan, MD
Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine
Chief, Division of Orthopaedic Molecular Medicine
Perelman School of Medicine
The University of Pennsylvania
c/o Department of Orthopaedic Surgery
Penn Musculoskeletal Center – Suite 600
3737 Market Street
Philadelphia, PA 19104
email: [email protected]
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